Epidemiologic studies have implicated obesity as a factor driving the progression of prostate cancer from an indolent to a life-threatening disease but how this may occur remains obscure. Several hypotheses have been advanced including reduced levels of testosterone, elevated levels of insulin-like growth factor 1 (IGF-1) or elevated levels of adipokines particularly leptin. Determining the relative importance of these mechanisms or identifying others will be difficult in humans. For this reason, it is critical to develop experimentally tractable animal models with which to evaluate these questions. We have developed a new mouse model (B6: PTEN/luc), combining several previously described elements, which is ideally suited to address these questions. The key features of this model are the following: 1) Prostate cancer is initiated by prostate-specific deletion of the PTEN tumor suppressor gene, a gene commonly mutated in human prostate cancer, using Cre- lox technology;2) We have engineered this strain so that prostate cancer progression can be monitored non- invasively using bioluminescence imaging;and 3) We have extensively backcrossed our model to the C57BL/6J strain which will facilitate analysis of the tumor phenotype and is the best characterized mouse strain for obesity research. In this proposal we seek to further the development of this model by pursuing the following specific aims: 1) Characterize prostate cancer progression in both homozygous and heterozygous B6: PTEN/luc mice. Here we will perform the baseline analysis necessary to characterize the variability and validate the utility of bioluminescence imaging to monitor prostate cancer progression in these mice;2) Measure the effects of diet-induced obesity on prostate cancer progression in heterozygous B6: PTEN/luc mice. Here we will determine whether diet-induced obesity accelerates the progression of prostate cancer from a pre-neoplastic state to adenocarcinoma and determine whether this is correlated with levels of testosterone, IGF-1 and leptin;and 3) Measure the effects of diet-induced obesity on progression to androgen- independent prostate cancer in homozygous B6: PTEN/luc mice. Here we will determine whether diet-induced obesity affects the development of androgen-independent prostate cancer following castration. The successful completion of these studies will validate our model for the study of the linkage between obesity and prostate cancer progression and begin to evaluate the biological mechanisms associated with this. These studies will provide the basis for future hypothesis-directed studies aimed at further elucidation of these mechanisms. PUBLIC HEALTH RELEVANCE: Clinical studies suggest that obesity may promote the progression of prostate cancer from an indolent to a lethal disease, but the biological mechanisms for this are unclear. Elucidating these mechanisms will be important for the improved diagnosis and treatment of this disease. Because these mechanisms will be difficult to experimentally validate in humans, here propose to develop a novel mouse model to explore the relationship between obesity and prostate cancer progression.